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Warfarin: what are the clinical implications of an out-of-range-therapeutic international normalized ratio?

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Abstract

Warfarin is a commonly used oral anticoagulant, and has well-established clinical efficacy. However, it has a narrow therapeutic window, and a mode-of-action affected by inter-individual differences and environmental factors. The effectiveness and safety of warfarin are closely related to maintenance of the international normalized ratio (INR) within therapeutic range. A supra-therapeutic INR puts patients at risk of bleeding, whereas a sub-therapeutic INR may not protect against thromboembolic complications. Research suggests a lack of anticoagulation control during warfarin therapy in different settings. Careful monitoring of the INR is essential, especially in geriatric or cancer populations who are at an increased risk of major hemorrhage. Warfarin is an effective treatment but optimization of the risk-benefit ratio is crucial in order to maximize efficacy and safety. Here, we will assess the extent to which INRs are an issue in the management of warfarin therapy, and the effect INRs may have on clinical outcomes.

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References

  1. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E (2004) The pharmacology and management of the vitamin K antagonists: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126(3 Suppl):204S–233S

    Article  PubMed  CAS  Google Scholar 

  2. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ (2004) Antithrombotic therapy in atrial fibrillation: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126(3 Suppl):429S–456S

    Article  PubMed  CAS  Google Scholar 

  3. Gurwitz JH, Field TS, Harrold LR, Rothschild J, Debellis K, Seger AC et al (2003) Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA 289:1107–1116

    Article  PubMed  Google Scholar 

  4. Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV et al (2003) Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 349:1019–1026

    Article  PubMed  CAS  Google Scholar 

  5. Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M et al (2005) Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 165:1095–1106

    Article  PubMed  CAS  Google Scholar 

  6. Caldwell MD, Berg RL, Zhang KQ, Glurich I, Schmelzer JR, Yale SH et al (2007) Evaluation of genetic factors for warfarin dose prediction. Clin Med Res 5:8–16

    Article  PubMed  CAS  Google Scholar 

  7. van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ (2006) Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest 129:1155–1166

    Article  PubMed  Google Scholar 

  8. Sarawate C, Sikirica MV, Willey VJ, Bullano MF, Hauch O (2006) Monitoring anticoagulation in atrial fibrillation. J Thromb Thrombolysis 21:191–198

    Article  PubMed  CAS  Google Scholar 

  9. Samsa GP, Matchar DB, Goldstein LB, Bonito AJ, Lux LJ, Witter DM et al (2000) Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med 160:967–973

    Article  PubMed  CAS  Google Scholar 

  10. Pengo V, Pegoraro C, Cucchini U, Iliceto S (2006) Worldwide management of oral anticoagulant therapy: the ISAM study. J Thromb Thrombolysis 21:73–77

    Article  PubMed  Google Scholar 

  11. Witt DM, Sadler MA, Shanahan RL, Mazzoli G, Tillman DJ (2005) Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy. Chest 127:1515–1522

    Article  PubMed  Google Scholar 

  12. Hixson-Wallace JA, Dotson JB, Blakey SA (2001) Effect of regimen complexity on patient satisfaction and compliance with warfarin therapy. Clin Appl Thromb Hemost 7:33–37

    Article  PubMed  CAS  Google Scholar 

  13. Waterman AD, Milligan PE, Bayer L, Banet GA, Gatchel SK, Gage BF (2004) Effect of warfarin nonadherence on control of the international normalized ratio. Am J Health Syst Pharm 61:1258–1264

    PubMed  Google Scholar 

  14. Schmidt-Lucke C, Paar WD, Stellbrink C, Nixdorff U, Hofmann T, Meurer J et al (2007) Quality of anticoagulation with unfractionated heparin plus phenprocoumon for the prevention of thromboembolic complications in cardioversion for non-valvular atrial fibrillation. Sub-analysis from the anticoagulation in cardioversion using enoxaparin (ACE) trial. Thromb Res 119:27–34

    Article  PubMed  CAS  Google Scholar 

  15. Veeger NJ, Piersma-Wichers M, Hillege HL, Crijns HJ, van der Meer J (2006) Early detection of patients with a poor response to vitamin K antagonists: the clinical impact of individual time within target range in patients with heart disease. J Thromb Haemost 4:1625–1627

    Article  PubMed  CAS  Google Scholar 

  16. Wilson SJ, Wells PS, Kovacs MJ, Lewis GM, Martin J, Burton E, Anderson DR (2003) Comparing the quality of oral anticoagulant management by anticoagulation clinics and by family physicians: a randomized controlled trial. CMAJ 169:293–298

    PubMed  Google Scholar 

  17. Gottlieb LK, Salem-Schatz S (1994) Anticoagulation in atrial fibrillation. Does efficacy in clinical trials translate into effectiveness in practice? Arch Intern Med 154:1945–1953

    Article  PubMed  CAS  Google Scholar 

  18. Frost L, Johnsen SP, Pedersen L, Toft E, Husted S, Sørensen HT (2002) Atrial fibrillation or flutter and stroke: a Danish population-based study of the effectiveness of oral anticoagulation in clinical practice. J Intern Med 252:64–69

    Article  PubMed  CAS  Google Scholar 

  19. Atrial Fibrillation Investigators (1994) Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 154:1449–1457

    Article  Google Scholar 

  20. Bungard TJ, Ghali WA, Teo KK, McAlister FA, Tsuyuki RT (2000) Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med 160:41–46

    Article  PubMed  CAS  Google Scholar 

  21. Gurwitz JH, Monette J, Rochon PA, Eckler MA, Avorn J (1997) Atrial fibrillation and stroke prevention with warfarin in the long-term care setting. Arch Intern Med 157:978–984

    Article  PubMed  CAS  Google Scholar 

  22. Levine MN, Raskob G, Beyth RJ, Kearon C, Schulman S (2004) Hemorrhagic complications of anticoagulant treatment: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126(3 Suppl):287S–310S

    Article  PubMed  CAS  Google Scholar 

  23. Tapson VF, Hyers TM, Waldo AL, Ballard DJ, Becker RC, Caprini JA, NABOR (National Anticoagulation Benchmark and Outcomes Report) Steering Committee, et al (2005) Antithrombotic therapy practices in US hospitals in an era of practice guidelines. Arch Intern Med 165:1458–1464

    Google Scholar 

  24. Kucher N, Castellanos LR, Quiroz R, Koo S, Fanikos J, Goldhaber SZ (2004) Time trends in warfarin-associated hemorrhage. Am J Cardiol 94:403–406

    Article  PubMed  Google Scholar 

  25. Poli D, Antonucci E, Gensini GF, Abbate R, Prisco D (2003) Asymptomatic excessive coumarin anticoagulation is a risk factor for thrombotic and bleeding complications of oral anticoagulant therapy. J Thromb Haemost 1:1840–1841

    Article  PubMed  CAS  Google Scholar 

  26. Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D'Angelo A et al (1996) Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian study on complications of oral anticoagulant therapy. Lancet 348:423–428

    Article  PubMed  CAS  Google Scholar 

  27. Oden A, Fahlen M (2002) Oral anticoagulation and risk of death: a medical record linkage study. BMJ 325:1073–1075

    Article  PubMed  Google Scholar 

  28. Linkins LA, Choi PT, Douketis JD (2003) Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 139:893–900

    PubMed  Google Scholar 

  29. Kessler CM (2006) Urgent reversal of warfarin with prothrombin complex concentrate: where are the evidence-based data? J Thromb Haemost 4:963–966

    Article  PubMed  CAS  Google Scholar 

  30. Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ (2005) Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 91:472–477

    Article  PubMed  CAS  Google Scholar 

  31. de Vicente Cámara MP, Lucía Cuesta JF, Aguilar Franco C, Solano Bernad V, Serrano González C, García-Erce JA (1999) Major thromboembolic complications during oral anticoagulant therapy. Importance of level of anticoagulation. Sangre (Barc) 44:469–472

    Google Scholar 

  32. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investiagtors et al (2002) A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 347:1825–1833

  33. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group et al (2002) A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 347:1834–1840

    Google Scholar 

  34. Palareti G, Legnani C, Cosmi B, Guazzaloca G, Cini M, Mattarozzi S (2005) Poor anticoagulation quality in the first 3 months after unprovoked venous thromboembolism is a risk factor for long-term recurrence. J Thromb Haemost 3:955–961

    Article  PubMed  CAS  Google Scholar 

  35. Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B et al (2002) Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 100:3484–3488

    Article  PubMed  CAS  Google Scholar 

  36. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Randomized comparison of low-molecular-weight heparin versus oral anticoagulant therapy for the prevention of recurrent venous thromboembolism in patients with cancer (CLOT) investigators et al (2003) Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146–153

    Google Scholar 

  37. Bona RD, Sivjee KY, Hickey AD, Wallace DM, Wajcs SB (1995) The efficacy and safety of oral anticoagulation in patients with cancer. Thromb Haemost 74:1055–1058

    PubMed  CAS  Google Scholar 

  38. Siguret V, Gouin I, Debray M, Perret-Guillaume C, Boddaert J, Mahé I et al (2005) Initiation of warfarin therapy in elderly medical inpatients: a safe and accurate regimen. Am J Med 118:137–142

    Article  PubMed  CAS  Google Scholar 

  39. Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM (2005) Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest 127:2049–2056

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors received editorial support in the preparation of this manuscript, funded by sanofi-aventis, NJ, USA. The authors, however, were fully responsible for content and editorial decisions for this manuscript.

Disclosures

Geno J. Merli conducted research studies with sanofi-aventis, Bristol Myers Squibb, and Bayer. George L. Tzanis conducted research studies with sanofi-aventis, Bristol Myers Squibb, and Bayer.

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  1. Jefferson Center for Vascular Diseases, Jefferson Medical College, Thomas Jefferson University Hospital, Philadelphia, PA, 19107, USA

    Geno J. Merli & George Tzanis

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  1. Geno J. Merli
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Correspondence to Geno J. Merli.

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Merli, G.J., Tzanis, G. Warfarin: what are the clinical implications of an out-of-range-therapeutic international normalized ratio?. J Thromb Thrombolysis 27, 293–299 (2009). https://doi.org/10.1007/s11239-008-0219-9

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  • DOI: https://doi.org/10.1007/s11239-008-0219-9

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